AAV-based in vivo gene therapy for neurological disorders

Abstract

Recent advancements in gene supplementation therapy are expanding the options for the treatment of neurological disorders. Among the available delivery vehicles, adeno-associated virus (AAV) is often the favoured vector. However, the results have been variable, with some trials dramatically altering the course of disease whereas others have shown negligible efficacy or even unforeseen toxicity. Unlike traditional drug development with small molecules, therapeutic profiles of AAV gene therapies are dependent on both the AAV capsid and the therapeutic transgene. In this rapidly evolving field, numerous clinical trials of gene supplementation for neurological disorders are ongoing. Knowledge is growing about factors that impact the translation of preclinical studies to humans, including the administration route, timing of treatment, immune responses and limitations of available model systems. The field is also developing potential solutions to mitigate adverse effects, including AAV capsid engineering and designs to regulate transgene expression. At the same time, preclinical research is addressing new frontiers of gene supplementation for neurological disorders, with a focus on mitochondrial and neurodevelopmental disorders. In this Review, we describe the current state of AAV-mediated neurological gene supplementation therapy, including critical factors for optimizing the safety and efficacy of treatments, as well as unmet needs in this field.

This is a preview of subscription content, access via your institution

Access options

/* style specs start */
style{display:none!important}.LiveAreaSection-193358632 *{align-content:stretch;align-items:stretch;align-self:auto;animation-delay:0s;animation-direction:normal;animation-duration:0s;animation-fill-mode:none;animation-iteration-count:1;animation-name:none;animation-play-state:running;animation-timing-function:ease;azimuth:center;backface-visibility:visible;background-attachment:scroll;background-blend-mode:normal;background-clip:borderBox;background-color:transparent;background-image:none;background-origin:paddingBox;background-position:0 0;background-repeat:repeat;background-size:auto auto;block-size:auto;border-block-end-color:currentcolor;border-block-end-style:none;border-block-end-width:medium;border-block-start-color:currentcolor;border-block-start-style:none;border-block-start-width:medium;border-bottom-color:currentcolor;border-bottom-left-radius:0;border-bottom-right-radius:0;border-bottom-style:none;border-bottom-width:medium;border-collapse:separate;border-image-outset:0s;border-image-repeat:stretch;border-image-slice:100%;border-image-source:none;border-image-width:1;border-inline-end-color:currentcolor;border-inline-end-style:none;border-inline-end-width:medium;border-inline-start-color:currentcolor;border-inline-start-style:none;border-inline-start-width:medium;border-left-color:currentcolor;border-left-style:none;border-left-width:medium;border-right-color:currentcolor;border-right-style:none;border-right-width:medium;border-spacing:0;border-top-color:currentcolor;border-top-left-radius:0;border-top-right-radius:0;border-top-style:none;border-top-width:medium;bottom:auto;box-decoration-break:slice;box-shadow:none;box-sizing:border-box;break-after:auto;break-before:auto;break-inside:auto;caption-side:top;caret-color:auto;clear:none;clip:auto;clip-path:none;color:initial;column-count:auto;column-fill:balance;column-gap:normal;column-rule-color:currentcolor;column-rule-style:none;column-rule-width:medium;column-span:none;column-width:auto;content:normal;counter-increment:none;counter-reset:none;cursor:auto;display:inline;empty-cells:show;filter:none;flex-basis:auto;flex-direction:row;flex-grow:0;flex-shrink:1;flex-wrap:nowrap;float:none;font-family:initial;font-feature-settings:normal;font-kerning:auto;font-language-override:normal;font-size:medium;font-size-adjust:none;font-stretch:normal;font-style:normal;font-synthesis:weight style;font-variant:normal;font-variant-alternates:normal;font-variant-caps:normal;font-variant-east-asian:normal;font-variant-ligatures:normal;font-variant-numeric:normal;font-variant-position:normal;font-weight:400;grid-auto-columns:auto;grid-auto-flow:row;grid-auto-rows:auto;grid-column-end:auto;grid-column-gap:0;grid-column-start:auto;grid-row-end:auto;grid-row-gap:0;grid-row-start:auto;grid-template-areas:none;grid-template-columns:none;grid-template-rows:none;height:auto;hyphens:manual;image-orientation:0deg;image-rendering:auto;image-resolution:1dppx;ime-mode:auto;inline-size:auto;isolation:auto;justify-content:flexStart;left:auto;letter-spacing:normal;line-break:auto;line-height:normal;list-style-image:none;list-style-position:outside;list-style-type:disc;margin-block-end:0;margin-block-start:0;margin-bottom:0;margin-inline-end:0;margin-inline-start:0;margin-left:0;margin-right:0;margin-top:0;mask-clip:borderBox;mask-composite:add;mask-image:none;mask-mode:matchSource;mask-origin:borderBox;mask-position:0 0;mask-repeat:repeat;mask-size:auto;mask-type:luminance;max-height:none;max-width:none;min-block-size:0;min-height:0;min-inline-size:0;min-width:0;mix-blend-mode:normal;object-fit:fill;object-position:50% 50%;offset-block-end:auto;offset-block-start:auto;offset-inline-end:auto;offset-inline-start:auto;opacity:1;order:0;orphans:2;outline-color:initial;outline-offset:0;outline-style:none;outline-width:medium;overflow:visible;overflow-wrap:normal;overflow-x:visible;overflow-y:visible;padding-block-end:0;padding-block-start:0;padding-bottom:0;padding-inline-end:0;padding-inline-start:0;padding-left:0;padding-right:0;padding-top:0;page-break-after:auto;page-break-before:auto;page-break-inside:auto;perspective:none;perspective-origin:50% 50%;pointer-events:auto;position:static;quotes:initial;resize:none;right:auto;ruby-align:spaceAround;ruby-merge:separate;ruby-position:over;scroll-behavior:auto;scroll-snap-coordinate:none;scroll-snap-destination:0 0;scroll-snap-points-x:none;scroll-snap-points-y:none;scroll-snap-type:none;shape-image-threshold:0;shape-margin:0;shape-outside:none;tab-size:8;table-layout:auto;text-align:initial;text-align-last:auto;text-combine-upright:none;text-decoration-color:currentcolor;text-decoration-line:none;text-decoration-style:solid;text-emphasis-color:currentcolor;text-emphasis-position:over right;text-emphasis-style:none;text-indent:0;text-justify:auto;text-orientation:mixed;text-overflow:clip;text-rendering:auto;text-shadow:none;text-transform:none;text-underline-position:auto;top:auto;touch-action:auto;transform:none;transform-box:borderBox;transform-origin:50% 50%0;transform-style:flat;transition-delay:0s;transition-duration:0s;transition-property:all;transition-timing-function:ease;vertical-align:baseline;visibility:visible;white-space:normal;widows:2;width:auto;will-change:auto;word-break:normal;word-spacing:normal;word-wrap:normal;writing-mode:horizontalTb;z-index:auto;-webkit-appearance:none;-moz-appearance:none;-ms-appearance:none;appearance:none;margin:0}.LiveAreaSection-193358632{width:100%}.LiveAreaSection-193358632 .login-option-buybox{display:block;width:100%;font-size:17px;line-height:30px;color:#222;padding-top:30px;font-family:Harding,Palatino,serif}.LiveAreaSection-193358632 .additional-access-options{display:block;font-weight:700;font-size:17px;line-height:30px;color:#222;font-family:Harding,Palatino,serif}.LiveAreaSection-193358632 .additional-login>li:not(:first-child)::before{transform:translateY(-50%);content:””;height:1rem;position:absolute;top:50%;left:0;border-left:2px solid #999}.LiveAreaSection-193358632 .additional-login>li:not(:first-child){padding-left:10px}.LiveAreaSection-193358632 .additional-login>li{display:inline-block;position:relative;vertical-align:middle;padding-right:10px}.BuyBoxSection-683559780{display:flex;flex-wrap:wrap;flex:1;flex-direction:row-reverse;margin:-30px -15px 0}.BuyBoxSection-683559780 .box-inner{width:100%;height:100%}.BuyBoxSection-683559780 .readcube-buybox{background-color:#f3f3f3;flex-shrink:1;flex-grow:1;flex-basis:255px;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .subscribe-buybox{background-color:#f3f3f3;flex-shrink:1;flex-grow:4;flex-basis:300px;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .subscribe-buybox-nature-plus{background-color:#f3f3f3;flex-shrink:1;flex-grow:4;flex-basis:100%;background-clip:content-box;padding:0 15px;margin-top:30px}.BuyBoxSection-683559780 .title-readcube,.BuyBoxSection-683559780 .title-buybox{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:24px;line-height:32px;color:#222;padding-top:30px;text-align:center;font-family:Harding,Palatino,serif}.BuyBoxSection-683559780 .title-asia-buybox{display:block;margin:0;margin-right:5%;margin-left:5%;font-size:24px;line-height:32px;color:#222;padding-top:30px;text-align:center;font-family:Harding,Palatino,serif}.BuyBoxSection-683559780 .asia-link{color:#069;cursor:pointer;text-decoration:none;font-size:1.05em;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:1.05em6}.BuyBoxSection-683559780 .access-readcube{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:14px;color:#222;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .access-asia-buybox{display:block;margin:0;margin-right:5%;margin-left:5%;font-size:14px;color:#222;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .access-buybox{display:block;margin:0;margin-right:10%;margin-left:10%;font-size:14px;color:#222;opacity:.8px;padding-top:10px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .price-buybox{display:block;font-size:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;padding-top:30px;text-align:center}.BuyBoxSection-683559780 .price-buybox-to{display:block;font-size:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;text-align:center}.BuyBoxSection-683559780 .price-info-text{font-size:16px;padding-right:10px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-value{font-size:30px;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-per-period{font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .price-from{font-size:14px;padding-right:10px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:20px}.BuyBoxSection-683559780 .issue-buybox{display:block;font-size:13px;text-align:center;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:19px}.BuyBoxSection-683559780 .no-price-buybox{display:block;font-size:13px;line-height:18px;text-align:center;padding-right:10%;padding-left:10%;padding-bottom:20px;padding-top:30px;color:#222;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif}.BuyBoxSection-683559780 .vat-buybox{display:block;margin-top:5px;margin-right:20%;margin-left:20%;font-size:11px;color:#222;padding-top:10px;padding-bottom:15px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:17px}.BuyBoxSection-683559780 .tax-buybox{display:block;width:100%;color:#222;padding:20px 16px;text-align:center;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;line-height:NaNpx}.BuyBoxSection-683559780 .button-container{display:flex;padding-right:20px;padding-left:20px;justify-content:center}.BuyBoxSection-683559780 .button-container>*{flex:1px}.BuyBoxSection-683559780 .button-container>a:hover,.Button-505204839:hover,.Button-1078489254:hover,.Button-2496381730:hover{text-decoration:none}.BuyBoxSection-683559780 .readcube-button{background:#fff;margin-top:30px}.BuyBoxSection-683559780 .button-asia{background:#069;border:1px solid #069;border-radius:0;cursor:pointer;display:block;padding:9px;outline:0;text-align:center;text-decoration:none;min-width:80px;margin-top:75px}.BuyBoxSection-683559780 .button-label-asia,.ButtonLabel-3869432492,.ButtonLabel-3296148077,.ButtonLabel-1651148777{display:block;color:#fff;font-size:17px;line-height:20px;font-family:-apple-system,BlinkMacSystemFont,”Segoe UI”,Roboto,Oxygen-Sans,Ubuntu,Cantarell,”Helvetica Neue”,sans-serif;text-align:center;text-decoration:none;cursor:pointer}.Button-505204839,.Button-1078489254,.Button-2496381730{background:#069;border:1px solid #069;border-radius:0;cursor:pointer;display:block;padding:9px;outline:0;text-align:center;text-decoration:none;min-width:80px;max-width:320px;margin-top:10px}.Button-505204839 .readcube-label,.Button-1078489254 .readcube-label,.Button-2496381730 .readcube-label{color:#069}
/* style specs end */

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Gene replacement and supplementation therapy.
Fig. 2: AAV vector design.
Fig. 3: Routes of administration for brain-targeted gene therapy.
Fig. 4: Mitigating AAV off-targeting and toxicity.

References

  1. Janson, C. et al. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum. Gene Ther. 13, 1391–1412 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  2. Leone, P. et al. Long-term follow-up after gene therapy for Canavan disease. Sci. Transl. Med. 4, 165ra163 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  3. Cavazzana, M., Bushman, F. D., Miccio, A., André-Schmutz, I. & Six, E. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges. Nat. Rev. Drug. Discov. 18, 447–462 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  4. Kinsella, J. L. et al. Ex-vivo autologous stem cell gene therapy clinical trial for mucopolysaccharidosis type IIIA: trial in progress-NCT04201405. Blood 136, 15–16 (2020).

    Article 

    Google Scholar 

  5. Gentner, B. et al. Hematopoietic stem- and progenitor-cell gene therapy for Hurler syndrome. N. Engl. J. Med. 385, 1929–1940 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  6. Fumagalli, F. et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet 399, 372–383 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  7. Eichler, F. et al. Hematopoietic stem-cell gene therapy for cerebral adrenoleukodystrophy. N. Engl. J. Med. 377, 1630–1638 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  8. Charlesworth, C. T., Hsu, I., Wilkinson, A. C. & Nakauchi, H. Immunological barriers to haematopoietic stem cell gene therapy. Nat. Rev. Immunol. 12, 719–733 (2022).

    Article 

    Google Scholar 

  9. Bulcha, J. T., Wang, Y., Ma, H., Tai, P. W. & Gao, G. Viral vector platforms within the gene therapy landscape. Signal. Transduct. Target. Ther. 6, 1–24 (2021).

    Article 

    Google Scholar 

  10. Sung, Y. K. & Kim, S. Recent advances in the development of gene delivery systems. Biomater. Res. 23, 1–7 (2019).

    Article 

    Google Scholar 

  11. Atchison, R. W., Casto, B. C. & Hammon, W. M. Adenovirus-associated defective virus particles. Science 149, 754–756 (1965).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  12. Flotte, T. R. Gene therapy progress and prospects: recombinant adeno-associated virus (rAAV) vectors. Gene Ther. 11, 805–810 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  13. Duque, S. et al. Intravenous administration of self-complementary AAV9 enables transgene delivery to adult motor neurons. Mol. Ther. 17, 1187–1196 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  14. Foust, K. D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27, 59–65 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  15. Gao, G. et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J. Virol. 78, 6381–6388 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  16. Yao, Y. et al. Variants of the adeno-associated virus serotype 9 with enhanced penetration of the blood–brain barrier in rodents and primates. Nat. Biomed. Eng. 6, 1257–1271 (2022). This paper uses a rational design approach to identify two new AAV9 variants that can cross the BBB.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  17. Kumar, S. R. et al. Multiplexed Cre-dependent selection yields systemic AAVs for targeting distinct brain cell types. Nat. Methods 17, 541–550 (2020).

    Article 
    PubMed Central 

    Google Scholar 

  18. Goertsen, D. et al. AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset. Nat. Neurosci. 25, 106–115 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  19. Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  20. Chen, X. et al. Engineered AAVs for non-invasive functional transgene expression in rodent and non-human primate central and peripheral nervous systems. Neuron 110, 2242–2257 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  21. Meyer, N. L. & Chapman, M. S. Adeno-associated virus (AAV) cell entry: structural insights. Trends Microbiol. 30, 432–451 (2021).

    Article 
    PubMed 

    Google Scholar 

  22. Summerford, C. & Samulski, R. J. Membrane-associated heparan sulfate proteoglycan is a receptor for adeno-associated virus type 2 virions. J. Virol. 72, 1438–1445 (1998).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  23. Kaludov, N., Brown, K. E., Walters, R. W., Zabner, J. & Chiorini, J. A. Adeno-associated virus serotype 4 (AAV4) and AAV5 both require sialic acid binding for hemagglutination and efficient transduction but differ in sialic acid linkage specificity. J. Virol. 75, 6884–6893 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  24. Wu, Z., Miller, E., Agbandje-McKenna, M. & Samulski, R. J. α2,3 and α2,6 N-linked sialic acids facilitate efficient binding and transduction by adeno-associated virus types 1 and 6. J. Virol. 80, 9093–9103 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  25. Shen, S., Bryant, K. D., Brown, S. M., Randell, S. H. & Asokan, A. Terminal N-linked galactose is the primary receptor for adeno-associated virus 9. J. Biol. Chem. 286, 13532–13540 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  26. Riyad, J. M. & Weber, T. Intracellular trafficking of adeno-associated virus (AAV) vectors: challenges and future directions. Gene Ther. 28, 683–696 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  27. Penaud-Budloo, M. et al. Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle. J. Virol. 82, 7875–7885 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  28. Dalwadi, D. A. et al. AAV integration in human hepatocytes. Mol. Ther. 29, 2898–2909 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  29. McCarty, D. M., Monahan, P. E. & Samulski, R. J. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther. 8, 1248–1254 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  30. McCarty, D. M. et al. Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo. Gene Ther. 10, 2112–2118 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  31. Chen, X. et al. Biodistribution of adeno-associated virus gene therapy following cerebrospinal fluid-directed administration. Hum. Gene Ther. 34, 94–111 (2023). This paper conducts a comprehensive literature review to compare the biodistribution of AAV from different intra-CSF administration routes.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  32. Bharucha-Goebel, D. et al. O.10 First-in-human intrathecal gene transfer study for giant axonal neuropathy: preliminary review of long-term efficacy and safety. Neuromuscul. Disord. 32, S94 (2022).

    Article 

    Google Scholar 

  33. Bailey, R. M., Armao, D., Nagabhushan Kalburgi, S. & Gray, S. J. Development of intrathecal AAV9 gene therapy for giant axonal neuropathy. Mol. Ther. Methods Clin. Dev. 9, 160–171 (2018). This paper is the first study to show the safety and efficacy of using intrathecal lumbar administration route for delivering gene therapy to treat neurological disorders.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  34. Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017). This paper reports clinical data from the clinical trial for SMA, the first gene therapy approved for a neurological disorder.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  35. Al-Zaidy, S. A. & Mendell, J. R. From clinical trials to clinical practice: practical considerations for gene replacement therapy in SMA type 1. Pediatr. Neurol. 100, 3–11 (2019).

    Article 
    PubMed 

    Google Scholar 

  36. Burghes, A. H. & Beattie, C. E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat. Rev. Neurosci. 10, 597–609 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  37. Hinderer, C. et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum. Gene Ther. 29, 285–298 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  38. Niethammer, M. et al. Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity. Sci. Transl. Med. 10, eaau0713 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  39. Ciesielska, A. et al. Anterograde axonal transport of AAV2–GDNF in rat basal ganglia. Mol. Ther. 19, 922–927 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  40. Okada, S. & O’Brien, J. S. Generalized gangliosidosis: β-galactosidase deficiency. Science 160, 1002–1004 (1968).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  41. Gray-Edwards, H. L. et al. Novel biomarkers of human GM1 gangliosidosis reflect the clinical efficacy of gene therapy in a feline model. Mol. Ther. 25, 892–903 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  42. Gross, A. L. et al. Intravenous delivery of adeno-associated viral gene therapy in feline GM1 gangliosidosis. Brain 145, 655–669 (2022).

    Article 
    PubMed 

    Google Scholar 

  43. Taghian, T. et al. Real-time MR tracking of AAV gene therapy with βgal-responsive MR probe in a murine model of GM1-gangliosidosis. Mol. Ther. Methods Clin. Dev. 23, 128–134 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  44. Mussche, S. et al. Restoration of cytoskeleton homeostasis after gigaxonin gene transfer for giant axonal neuropathy. Hum. Gene Ther. 24, 209–219 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  45. Fu, H. et al. Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9–hSGSH gene delivery. Mol. Ther. Methods Clin. Dev. 3, 16036 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  46. Woodley, E. et al. Efficacy of a bicistronic vector for correction of sandhoff disease in a mouse model. Mol. Ther. Methods Clin. Dev. 12, 47–57 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  47. Rosenberg, J. B. et al. AAVrh.10-mediated APOE2 central nervous system gene therapy for APOE4-associated Alzheimer’s disease. Hum. Gene Ther. Clin. Dev. 29, 24–47 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  48. Flotte, T. R. et al. AAV gene therapy for Tay–Sachs disease. Nat. Med. 28, 251–259 (2022). This paper summarizes clinical findings from the first AAV gene therapy clinical trial treating two children with Tay–Sachs disease.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  49. Taghian, T. et al. A safe and reliable technique for CNS delivery of AAV vectors in the cisterna magna. Mol. Ther. 28, 411–421 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  50. Flotte, T. R. et al. Phase 1/2 clinical trial of combined bilateral intrathalamic/intracisternal/intrathecal delivery of a rAAVrh8 vector in infantile and juvenile Tay-Sachs and sandhoff disease: report of ongoing studies. In ESGCT 29th Annual Congress in collaboration with BSGCT Edinburgh, UK, October 11–14, 2022 Abstracts Vol. 33, A71 (Mary Ann Liebert, 2022).

  51. Garcia-Sanz, P., Aerts, J. M. F. G. & Moratalla, R. The role of cholesterol in α-synuclein and lewy body pathology in GBA1 Parkinson’s disease. Mov. Disord. 36, 1070–1085 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  52. Li, D., Zhang, J. & Liu, Q. Brain cell type-specific cholesterol metabolism and implications for learning and memory. Trends Neurosci. 45, 401–414 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  53. Sucunza, D. et al. Glucocerebrosidase gene therapy induces α-synuclein clearance and neuroprotection of midbrain dopaminergic neurons in mice and macaques. Int. J. Mol. Sci. 22, 4825 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  54. Sheehan, P. et al. PR001 gene therapy improved phenotypes in models of Parkinson’s disease with GBA1 mutation: molecular and cell biology/endosomal–lysosomal dysfunction. Alzheimer’s Dement. 16, e043614 (2020).

    Article 

    Google Scholar 

  55. Tardieu, M. et al. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum. Gene Ther. 25, 506–516 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  56. Tardieu, M. et al. Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Lancet Neurol. 16, 712–720 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  57. Gougeon, M.-L. et al. Cell-mediated immunity to NAGLU transgene following intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome. Front. Immunol. 12, 655478 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  58. Sondhi, D. et al. Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing CLN2. Sci. Transl. Med. 12, eabb5413 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  59. Castle, M. J. et al. Postmortem analysis in a clinical trial of AAV2-NGF gene therapy for Alzheimer’s disease identifies a need for improved vector delivery. Hum. Gene Ther. 31, 415–422 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  60. Kantor, B., McCown, T., Leone, P. & Gray, S. J. Clinical applications involving CNS gene transfer. Adv. Genet. 87, 71–124 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  61. Hyland, K. & Clayton, P. Aromatic amino acid decarboxylase deficiency in twins. J. Inherit. Metab. Dis. 13, 301–304 (1990).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  62. Tai, C.-H. et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol. Ther. 30, 509–518 (2022). This paper summarizes the clinical findings from 26 patients with AADC deficiency receiving AAV gene therapy treatment through IPa administration, which led to the approval of this treatment by the EMA.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  63. Baek, R. C. et al. AAV-mediated gene delivery in adult GM1-gangliosidosis mice corrects lysosomal storage in CNS and improves survival. PLoS ONE 5, e13468 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  64. Cearley, C. N. & Wolfe, J. H. A single injection of an adeno-associated virus vector into nuclei with divergent connections results in widespread vector distribution in the brain and global correction of a neurogenetic disease. J. Neurosci. 27, 9928–9940 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  65. Pearson, T. S. et al. Gene therapy for aromatic l-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2–AADC to midbrain dopaminergic neurons. Nat. Commun. 12, 4251 (2021). This paper summarizes clinical findings from the first AAV gene therapy clinical trial using a magnetic resonance-guided IPa gene delivery approach.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  66. Salegio, E. A. et al. Feasibility of targeted delivery of AAV5–GFP into the cerebellum of nonhuman primates following a single convection-enhanced delivery infusion. Hum. Gene Ther. 33, 86–93 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  67. Yazdan-Shahmorad, A. et al. Widespread optogenetic expression in macaque cortex obtained with MR-guided, convection enhanced delivery (CED) of AAV vector to the thalamus. J. Neurosci. Methods 293, 347–358 (2018).

    Article 
    PubMed 

    Google Scholar 

  68. Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M. & Sah, D. W. Y. Gene therapy for neurological disorders: progress and prospects. Nat. Rev. Drug. Discov. 17, 641 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  69. Ravina, B. et al. Intraputaminal AADC gene therapy for advanced Parkinson’s disease: interim results of a phase 1b trial [abstract]. Hum. Gene Ther. 28, OR12 (2017).

    Google Scholar 

  70. Davidson, B. L. et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc. Natl Acad. Sci. USA 97, 3428–3432 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  71. Christine, C. W. et al. Safety of AADC gene therapy for moderately advanced Parkinson disease: three-year outcomes from the PD-1101 trial. Neurology 98, e40–e50 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  72. Luo, J. et al. Subthalamic GAD gene therapy in a Parkinson’s disease rat model. Science 298, 425–429 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  73. Niethammer, M. et al. Long-term follow-up of a randomized AAV2–GAD gene therapy trial for Parkinson’s disease. JCI Insight 2, e90133 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  74. Rocco, M. T. et al. Long-term safety of MRI-guided administration of AAV2–GDNF and gadoteridol in the putamen of individuals with Parkinson’s disease. Mol. Ther. 30, 3632–3638 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  75. Bartus, R. T. et al. Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating “clinical proof-of-concept” for AAV–neurturin (CERE-120) in Parkinson’s disease. Neurobiol. Aging 34, 35–61 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  76. Bartus, R. T. et al. Safety/feasibility of targeting the substantia nigra with AAV2–neurturin in Parkinson patients. Neurology 80, 1698–1701 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  77. Gray, S. J., Woodard, K. T. & Samulski, J. R. Viral vectors and delivery strategies for CNS gene therapy. Ther. Deliv. 1, 517–534 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  78. Heller, G. J. et al. Waning efficacy in a long-term AAV-mediated gene therapy study in the murine model of Krabbe disease. Mol. Ther. 29, 1883–1902 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  79. Chen, X. et al. AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease. J. Clin. Invest. 132, e146286 (2022). This paper presents a case showing how a preclinical study is translated into a clinical trial, with all the data that are required for an investigational new drug (IND) application included.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  80. Kishimoto, T. K. & Samulski, R. J. Addressing high dose AAV toxicity—‘one and done’or ‘slower and lower’? Expert. Opin. Biol. Ther. 22, 1067–1071 (2022).

    Article 
    PubMed 

    Google Scholar 

  81. Gray, S. J., Nagabhushan Kalburgi, S., McCown, T. J. & Jude Samulski, R. Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates. Gene Ther. 20, 450–459 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  82. Samaranch, L. et al. Adeno-associated virus serotype 9 transduction in the central nervous system of nonhuman primates. Hum. Gene Ther. 23, 382–389 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  83. Kondratov, O. et al. A comprehensive study of a 29-capsid AAV library in a non-human primate central nervous system. Mol. Ther. 29, 2806–2820 (2021). This paper compares the biodistribution of 29 different AAV serotypes in the CNS of NHPs when administered through IPa and intra-CSF administration routes.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  84. Gray, S. J. Timing of gene therapy interventions: the earlier, the better. Mol. Ther. 24, 1017–1018 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  85. Rashnonejad, A. et al. Fetal gene therapy using a single injection of recombinant AAV9 rescued SMA phenotype in mice. Mol. Ther. 27, 2123–2133 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  86. Lowes, L. P. et al. Impact of age and motor function in a phase 1/2A study of infants with SMA type 1 receiving single-dose gene replacement therapy. Pediatr. Neurol. 98, 39–45 (2019).

    Article 
    PubMed 

    Google Scholar 

  87. Chu, W. S. & Ng, J. Immunomodulation in administration of rAAV: preclinical and clinical adjuvant pharmacotherapies. Front. Immunol. 12, 858 (2021).

    Article 

    Google Scholar 

  88. Barnes, C., Scheideler, O. & Schaffer, D. Engineering the AAV capsid to evade immune responses. Curr. Opin. Biotech. 60, 99–103 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  89. Bertolini, T. B. et al. Effect of CpG depletion of vector genome on CD8+ T cell responses in AAV gene therapy. Front. Immunol. 12, 672449 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  90. Wright, J. F. Codon modification and PAMPs in clinical AAV vectors: the tortoise or the hare? Mol. Ther. 28, 701–703 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  91. Pan, X. et al. Rational engineering of a functional CpG-free ITR for AAV gene therapy. Gene Ther. 29, 333–345 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  92. Muhuri, M. et al. Overcoming innate immune barriers that impede AAV gene therapy vectors. J. Clin. Invest. 131, e143780 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  93. Kofoed, R. H. et al. Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis. Mol. Ther. Methods Clin. Dev. 23, 390–405 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  94. Ciesielska, A. et al. Cerebral infusion of AAV9 vector-encoding non-self proteins can elicit cell-mediated immune responses. Mol. Ther. 21, 158–166 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  95. Hadaczek, P. et al. Transduction of nonhuman primate brain with adeno-associated virus serotype 1: vector trafficking and immune response. Hum. Gene Ther. 20, 225–237 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  96. Samaranch, L. et al. AAV9-mediated expression of a non-self protein in nonhuman primate central nervous system triggers widespread neuroinflammation driven by antigen-presenting cell transduction. Mol. Ther. 22, 329–337 (2014). This paper is the first to demonstrate that using AAV to deliver a non-self protein, but not a self protein, may trigger neural immune responses in NHPs.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  97. Ramsingh, A. I. et al. Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. PLoS ONE 13, e0198154 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  98. Ling, Q., Rioux, M., Hu, Y., Lee, M. & Gray, S. J. Adeno-associated viral vector serotype 9-based gene replacement therapy for SURF1-related leigh syndrome. Mol. Ther. Methods Clin. Dev. 23, 158–168 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  99. Dell’Agnello, C. et al. Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431–444 (2007).

    Article 
    PubMed 

    Google Scholar 

  100. Quadalti, C. et al. SURF1 knockout cloned pigs: early onset of a severe lethal phenotype. Biochim. Biophys. Acta 1864, 2131–2142 (2018).

    Article 
    CAS 
    PubMed Central 

    Google Scholar 

  101. Bradbury, A. M. et al. Krabbe disease successfully treated via monotherapy of intrathecal gene therapy. J. Clin. Invest. 130, 4906–4920 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  102. Karumuthil‐Melethil, S. et al. Intrathecal administration of AAV/GALC vectors in 10–11‐day‐old twitcher mice improves survival and is enhanced by bone marrow transplant. J. Neurosci. Res. 94, 1138–1151 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  103. Li, M. & Belmonte, I.J.C. Organoids — preclinical models of human disease. N. Engl. J. Med. 380, 569–579 (2019).

    Article 
    PubMed 

    Google Scholar 

  104. Gorman, G. S. et al. Mitochondrial diseases. Nat. Rev. Dis. Prim. 2, 1–22 (2016).

    Google Scholar 

  105. Reynaud-Dulaurier, R. et al. Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome. Brain 143, 1686–1696 (2020).

    Article 
    PubMed 

    Google Scholar 

  106. Silva-Pinheiro, P., Cerutti, R., Luna-Sanchez, M., Zeviani, M. & Viscomi, C. A single intravenous injection of AAV–PHP.B–hNDUFS4 ameliorates the phenotype of Ndufs4−/− mice. Mol. Ther. Methods Clin. Dev. 17, 1071–1078 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  107. Pereira, C. V. et al. Myopathy reversion in mice after restauration of mitochondrial complex I. EMBO Mol. Med. 12, e10674 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  108. Meo, I. D., Marchet, S., Lamperti, C., Zeviani, M. & Viscomi, C. AAV9-based gene therapy partially ameliorates the clinical phenotype of a mouse model of Leigh syndrome. Gene Ther. 24, 661–667 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  109. Abrams, A. J. et al. Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat. Genet. 47, 926–932 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  110. Janer, A. et al. SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome. EMBO Mol. Med. 8, 1019–1038 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  111. Charlesworth, G. et al. SLC25A46 mutations underlie progressive myoclonic ataxia with optic atrophy and neuropathy. Mov. Disord. 31, 1249–1251 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  112. Hammer, M. B. et al. SLC25A46 mutations associated with autosomal recessive cerebellar ataxia in North African families. Neurodegener. Dis. 17, 208–212 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  113. Yang, L. et al. Systemic administration of AAV–Slc25a46 mitigates mitochondrial neuropathy in Slc25a46−/− mice. Hum. Mol. Genet. 29, 649–661 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  114. Vila-Julia, F. et al. Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides. EBioMedicine 62, 103133 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  115. Di Meo, I. et al. Effective AAV‐mediated gene therapy in a mouse model of ethylmalonic encephalopathy. EMBO Mol. Med. 4, 1008–1014 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  116. Chadderton, N. et al. Intravitreal delivery of AAV–NDI1 provides functional benefit in a murine model of Leber hereditary optic neuropathy. Eur. J. Hum. Genet. 21, 62–68 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  117. Koilkonda, R. D. et al. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial. JAMA Ophthalmol. 132, 409–420 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  118. Torres-Torronteras, J. et al. Long-term sustained effect of liver-targeted adeno-associated virus gene therapy for mitochondrial neurogastrointestinal encephalomyopathy. Hum. Gene Ther. 29, 708–718 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  119. Fountain, M. D. & Schaaf, C. P. Prader–Willi syndrome and Schaaf–Yang syndrome: neurodevelopmental diseases intersecting at the MAGEL2 gene. Diseases 4, 2 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  120. Queen, N. J. et al. Hypothalamic AAV–BDNF gene therapy improves metabolic function and behavior in the Magel2-null mouse model of Prader–Willi syndrome. Mol. Ther. Methods Clin. Dev. 27, 131–148 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  121. Zeier, Z. et al. Fragile X mental retardation protein replacement restores hippocampal synaptic function in a mouse model of fragile X syndrome. Gene Ther. 16, 1122–1129 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  122. Arsenault, J. et al. FMRP expression levels in mouse central nervous system neurons determine behavioral phenotype. Hum. Gene Ther. 27, 982–996 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  123. Gholizadeh, S., Arsenault, J., Xuan, I. C. Y., Pacey, L. K. & Hampson, D. R. Reduced phenotypic severity following adeno-associated virus-mediated Fmr1 gene delivery in fragile X mice. Neuropsychopharmacology 39, 3100–3111 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  124. Turner, T. J., Zourray, C., Schorge, S. & Lignani, G. Recent advances in gene therapy for neurodevelopmental disorders with epilepsy. J. Neurochem. 157, 229–262 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  125. Davidson, B. L. et al. Gene-based therapeutics for rare genetic neurodevelopmental psychiatric disorders. Mol. Ther. 30, 2416–2428 (2022). This paper summarizes the discussions and presentations ofGene-Based Therapeutics for Rare Genetic Neurodevelopmental Psychiatric Disorders, a National Institute of Mental Health-sponsored workshop held in January 2021.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  126. Prabhakar, S. et al. Long-term therapeutic efficacy of intravenous AAV-mediated hamartin replacement in mouse model of tuberous sclerosis type 1. Mol. Ther. Methods Clin. Dev. 15, 18–26 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  127. Gao, Y. et al. Gene replacement ameliorates deficits in mouse and human models of cyclin-dependent kinase-like 5 disorder. Brain 143, 811–832 (2020).

    Article 
    PubMed 

    Google Scholar 

  128. Taysha Gene Therapies Announces Initiation of Clinical Development of TSHA-102 in Rett Syndrome. Taysha https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-initiation-clinical-0 (2022).

  129. Sinnett, S. E., Boyle, E., Lyons, C. & Gray, S. J. Engineered microRNA-based regulatory element permits safe high-dose mini MECP2 gene therapy in Rett mice. Brain 144, 3005–3019 (2021). This paper shows the development of a self-regulatory gene therapy approach using endogenous miRNAs.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  130. Luoni, M. et al. Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome. eLife 9, e52629 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  131. Heeroma, J. H. et al. Episodic ataxia type 1 mutations differentially affect neuronal excitability and transmitter release. Dis. Model. Mech. 2, 612–619 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  132. Qiu, Y. et al. On-demand cell-autonomous gene therapy for brain circuit disorders. Science 378, 523–532 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  133. Judson, M. C. et al. Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice. JCI Insight 6, e144712 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  134. Ogiwara, I. et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J. Neurosci. 27, 5903–5914 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  135. Tanenhaus, A. et al. Cell-selective AAV-mediated SCN1A gene regulation therapy rescues mortality and seizure phenotypes in a dravet syndrome mouse model and is well tolerated in non-human primates. Hum. Gene Ther. 33, 579–597 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  136. Howden, S., Voullaire, L. & Vadolas, J. The transient expression of mRNA coding for Rep protein from AAV facilitates targeted plasmid integration. J. Gene Med. 10, 42–50 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  137. Dalwadi, D. A. et al. Liver injury increases the incidence of HCC following AAV gene therapy in mice. Mol. Ther. 29, 680–690 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  138. Donsante, A. et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science 317, 477–477 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  139. Nguyen, G. N. et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat. Biotechnol. 39, 47–55 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  140. Day, J. W. et al. Clinical trial and postmarketing safety of onasemnogene abeparvovec therapy. Drug. Saf. 44, 1109–1119 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  141. Guillou, J. et al. Fatal thrombotic microangiopathy case following adeno-associated viral SMN gene therapy. Blood Adv. 6, 4266–4270 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  142. Hordeaux, J. et al. Adeno-associated virus-induced dorsal root ganglion pathology. Hum. Gene Ther. 31, 808–818 (2020). This paper analyses potential factors leading to DRG pathology from AAV gene therapy by compiling data from 33 non-clinical studies in NHPs.

    Article 
    CAS 
    PubMed 

    Google Scholar 

  143. Buss, N. et al. Characterization of AAV-mediated dorsal root ganglionopathy. Mol. Ther. Methods Clin. Dev. 24, 342–354 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  144. Mueller, C. et al. SOD1 suppression with adeno-associated virus and microRNA in familial ALS. N. Engl. J. Med. 383, 151–158 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  145. Hordeaux, J. et al. microRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates. Sci. Transl. Med. 12, eaba9188 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  146. Kayani, S, et al. Preliminary safety data of a phase 1 first in-human clinical trial support the use of high dose intrathecal AAV9/CLN7 for the treatment of patients with CLN7 disease. Mol. Genet. Metabol. 135, S65 (2022).

    Article 

    Google Scholar 

  147. Rosenberg, J. B. et al. Safety of direct intraparenchymal AAVrh.10-mediated central nervous system gene therapy for metachromatic leukodystrophy. Hum. Gene Ther. 32, 563–580 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  148. Agbandje-McKenna, M. & Kleinschmidt, J. AAV capsid structure and cell interactions. Methods Mol. Biol. 807, 47–92 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  149. Salganik, M. et al. Adeno-associated virus capsid proteins may play a role in transcription and second-strand synthesis of recombinant genomes. J. Virol. 88, 1071–1079 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  150. Kanaan, N. M. et al. Rationally engineered AAV capsids improve transduction and volumetric spread in the CNS. Mol. Ther. Nucleic Acids 8, 184–197 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  151. Chan, Y. K. et al. Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses. Sci. Transl. Med. 13, eabd3438 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  152. Deverman, B. E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34, 204–209 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  153. Hordeaux, J. et al. The neurotropic properties of AAV–PHP.B are limited to C57BL/6J mice. Mol. Ther. 26, 664–668 (2018). This paper demonstrates that AAV vectors can show different tropisms in different species.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  154. Matsuzaki, Y. et al. Intravenous administration of the adeno-associated virus–PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci. Lett. 665, 182–188 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  155. Huang, Q. et al. Delivering genes across the blood–brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids. PLoS ONE 14, e0225206 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  156. Lin, R. et al. Directed evolution of adeno-associated virus for efficient gene delivery to microglia. Nat. Methods 19, 976–985 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  157. Beharry, A. et al. The AAV9 variant capsid AAV-F mediates widespread transgene expression in nonhuman primate spinal cord after intrathecal administration. Hum. Gene Ther. 33, 61–75 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  158. Stanton, A. C. et al. Systemic administration of novel engineered AAV capsids facilitates enhanced transgene expression in the macaque CNS. Medicine 4, 31–50 (2022).

    Article 

    Google Scholar 

  159. Mich, J. K. et al. Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex. Cell Rep. 34, 108754 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  160. Powell, S. K., Rivera-Soto, R. & Gray, S. J. Viral expression cassette elements to enhance transgene target specificity and expression in gene therapy. Discov. Med. 19, 49–57 (2015).

    PubMed 
    PubMed Central 

    Google Scholar 

  161. Jackson, K. L., Dayton, R. D., Deverman, B. E. & Klein, R. L. Better targeting, better efficiency for wide-scale neuronal transduction with the synapsin promoter and AAV-PHP.B. Front. Mol. Neurosci. 9, 116 (2016).

    PubMed 
    PubMed Central 

    Google Scholar 

  162. Xie, J. et al. microRNA-regulated, systemically delivered rAAV9: a step closer to CNS-restricted transgene expression. Mol. Ther. 19, 526–535 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  163. Sidonio, R. F. Jr et al. Discussing investigational AAV gene therapy with hemophilia patients: a guide. Blood Rev. 47, 100759 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  164. Athey, J. et al. A new and updated resource for codon usage tables. BMC Bioinforma. 18, 391 (2017).

    Article 

    Google Scholar 

  165. Mauro, V. P. & Chappell, S. A. A critical analysis of codon optimization in human therapeutics. Trends Mol. Med. 20, 604–613 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  166. Agashe, D., Martinez-Gomez, N. C., Drummond, D. A. & Marx, C. J. Good codons, bad transcript: large reductions in gene expression and fitness arising from synonymous mutations in a key enzyme. Mol. Biol. Evol. 30, 549–560 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  167. Spencer, P. S., Siller, E., Anderson, J. F. & Barral, J. M. Silent substitutions predictably alter translation elongation rates and protein folding efficiencies. J. Mol. Biol. 422, 328–335 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  168. Tsai, C.-J. et al. Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J. Mol. Biol. 383, 281–291 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  169. Zhou, J.-h et al. The effects of the synonymous codon usage and tRNA abundance on protein folding of the 3C protease of foot-and-mouth disease virus. Infect. Genet. Evol. 16, 270–274 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  170. Dominguez, E. et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum. Mol. Genet. 20, 681–693 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  171. Hordeaux, J. et al. Efficacy and safety of a Krabbe disease gene therapy. Hum. Gene Ther. 33, 499–517 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  172. Chand, D. et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J. Hepatol. 74, 560–566 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  173. Feldman, A. G. et al. Subacute liver failure following gene replacement therapy for spinal muscular atrophy type 1. J. Pediatr. 225, 252–258 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  174. Hordeaux, J. et al. Toxicology study of intra-cisterna magna adeno-associated virus 9 expressing iduronate-2-sulfatase in rhesus macaques. Mol. Ther. Methods Clin. Dev. 10, 68–78 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  175. Li, Y. et al. Enhanced efficacy and increased long-term toxicity of CNS-directed, AAV-based combination therapy for Krabbe disease. Mol. Ther. 29, 691–701 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  176. Boudreau, R. L., Spengler, R. M. & Davidson, B. L. Rational design of therapeutic siRNAs: minimizing off-targeting potential to improve the safety of RNAi therapy for Huntington’s disease. Mol. Ther. 19, 2169–2177 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  177. Boudreau, R. L., Martins, I. & Davidson, B. L. Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Mol. Ther. 17, 169–175 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  178. Franich, N. R. et al. AAV vector-mediated RNAi of mutant Huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease. Mol. Ther. 16, 947–956 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar 

  179. Miniarikova, J. et al. AAV5–miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington’s disease. Gene Ther. 24, 630–639 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  180. Meglio, M. uniQure receives DSMB recommendation to resume higher dosing of AMT-130 in huntington trial. Neurology Live https://www.neurologylive.com/view/uniqure-receives-dsmb-recommendation-resume-higher-dosing-amt-130-huntington-trial (2022).

  181. Curtis, H. J., Seow, Y., Wood, M. J. & Varela, M. A. Knockdown and replacement therapy mediated by artificial mirtrons in spinocerebellar ataxia 7. Nucleic Acids Res. 45, 7870–7885 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  182. Gaj, T., Guo, J., Kato, Y., Sirk, S. J. & Barbas, C. F. III Targeted gene knockout by direct delivery of zinc-finger nuclease proteins. Nat. Methods 9, 805–807 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  183. Liu, J., Gaj, T., Patterson, J. T., Sirk, S. J. & Barbas, C. F. III Cell-penetrating peptide-mediated delivery of TALEN proteins via bioconjugation for genome engineering. PLoS ONE 9, e85755 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  184. Carroll, D. Genome engineering with zinc-finger nucleases. Genetics 188, 773–782 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  185. Yamaguchi, T. et al. Aspects of gene therapy products using current genome-editing technology in Japan. Hum. Gene Ther. 31, 1043–1053 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  186. Newby, G. A. & Liu, D. R. In vivo somatic cell base editing and prime editing. Mol. Ther. 29, 3107–3124 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  187. Abudayyeh, O. O. et al. A cytosine deaminase for programmable single-base RNA editing. Science 365, 382–386 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar 

  188. Lubroth, P., Colasante, G. & Lignani, G. In vivo genome editing therapeutic approaches for neurological disorders: where are we in the translational pipeline? Front. Neurosci. 15, 632522 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors researched data for the article. S.J.G. and Q.L. contributed substantially to discussion of the content. Q.L. and J.H. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to
Steven J. Gray.

Ethics declarations

Competing interests

S.J.G. has received royalty income from inventions discussed in the article, through licensing agreements with Neurogene, Asklepios Biopharmaceuticals, Taysha Gene Therapies and Abeona Therapeutics. A.B. has received royalty income from inventions discussed in the article from Axovant Gene Therapies and Neurogene. Q.L. has received royalty income from inventions discussed in the article from Taysha Gene Therapies.

Peer review

Peer review information

Nature Reviews Drug Discovery thanks Stephanie Schorge and Olivier Danos for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Glossary

Capsid

The structural protein surrounding the genome of an encapsulated virus, including adeno-associated viruses (AAVs).

Convection-enhanced delivery

An experimental gene therapy delivery technique that uses a catheter to insert a thin tube into the brain and applies pressure to deliver the vector.

Cross-reactive immunological material

(CRIM). Typically refers to the presence of ‘self’ antigens by an individual, such that their immune system is tolerant to those antigens.

Episome

A closed circular extrachromosomal DNA molecule formed from a viral genome that serves as a transcription template.

Haploinsufficiency

When one copy of a gene is mutated, which leads to loss of function of the protein, only half the amount of functional protein is produced, and that is not enough to support normal cellular functions.

Hepatotoxicity

Liver-related adverse effects usually indicated by increased aspartate aminotransferase and alanine aminotransferase levels, sometimes accompanied by thrombocytopenia and coagulopathy.

Immediate early gene

A gene that is activated rapidly and transiently in response to a wide variety of cellular stimuli, such as neuronal activity.

Intraparenchymal

Within the functional tissue of an organ, which in this Review refers to the brain.

Kozak sequence

A nucleic acid motif for initiation of translation in vertebrates. The consensus sequence is GCCRCCAUGG, where R is a purine (A or G) and AUG is the initiation codon.

Open reading frame

A start codon followed by a portion of in-frame DNA sequence that does not include a stop codon.

Promoter

The upstream element to a gene that can control the timing and cell specificity of expression through the recruitment of transcriptional machinery.

Serotype

A virus classification based on surface antigen expression and determined by immunological responses in host serum.

Variant

Similar to serotype, a viral variant is classified according to surface antigen expression or other characteristics, but is not determined by immunological responses in host serum.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ling, Q., Herstine, J.A., Bradbury, A. et al. AAV-based in vivo gene therapy for neurological disorders.
Nat Rev Drug Discov (2023). https://doi.org/10.1038/s41573-023-00766-7

Download citation

  • Accepted: 06 July 2023

  • Published: 01 September 2023

  • DOI: https://doi.org/10.1038/s41573-023-00766-7

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Leave a Reply

Your email address will not be published. Required fields are marked *